Barvaux Vincent A, Ranson Malcolm, Brown Robert, McElhinney R Stanley, McMurry T Brian H, Margison Geoffrey P
Paterson Institute for Cancer Research and Christie Hospital, Manchester, United Kingdom.
Mol Cancer Ther. 2004 Feb;3(2):123-7.
Temozolomide is an alkylating agent that mediates its cytotoxic effects via O(6)-methylguanine (O(6)-meG) adducts in DNA and their recognition and processing by the postreplication mismatch repair system (MMR). O(6)-meG adducts can be repaired by the DNA repair protein O(6)-alkylguanine-DNA-alkyltransferase (MGMT), which therefore constitutes a major resistance mechanism to the drug. Resistance to Temozolomide can also be mediated by loss of MMR, which is frequently mediated by methylation of the hMLH1 gene promoter. Methylation of hMLH1 can be reversed by treatment of cells with 5-aza-2'-deoxycytidine, while the MGMT pseudosubstrate O(6)-(4-bromothenyl)guanine (PaTrin-2) can deplete MGMT activity. Using a drug-resistant cell line which expresses MGMT and has methylated hMLH1, we show that while either of these treatments can individually sensitize cells to Temozolomide, the combined treatment leads to substantially greater sensitization. The increased sensitization is not observed in matched MMR proficient cells.
替莫唑胺是一种烷化剂，它通过DNA中的O(6)-甲基鸟嘌呤（O(6)-meG）加合物以及复制后错配修复系统（MMR）对其的识别和处理来介导细胞毒性作用。O(6)-meG加合物可由DNA修复蛋白O(6)-烷基鸟嘌呤-DNA-烷基转移酶（MGMT）修复，因此这构成了对该药物的主要耐药机制。对替莫唑胺的耐药性也可由MMR缺失介导，这通常由hMLH1基因启动子甲基化介导。用5-氮杂-2'-脱氧胞苷处理细胞可逆转hMLH1的甲基化，而MGMT假底物O(6)-(4-溴噻吩基)鸟嘌呤（PaTrin-2）可消耗MGMT活性。使用一种表达MGMT且hMLH1甲基化的耐药细胞系，我们发现虽然这两种处理中的任何一种都能单独使细胞对替莫唑胺敏感，但联合处理会导致更高的敏感性。在匹配的MMR功能正常的细胞中未观察到这种增加的敏感性。
